Molecular Cell
Volume 69, Issue 5, 1 March 2018, Pages 729-743.e7
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Article
Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD

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Highlights

  • The MCL-1 BH3 helix directly interacts with and modulates VLCAD

  • Mcl-1 deletion deregulates long-chain fatty acid β-oxidation

  • The mitochondrial matrix form of MCL-1 has a separable function in lipid metabolism

  • MCL-1 exerts dual control over mitochondrial apoptosis and fatty acid metabolism

Summary

MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.

Keywords

MCL-1
BCL-2 family
apoptosis
mitochondria
mitochondrial matrix
VLCAD
fatty acid metabolism
β-oxidation
stapled peptide
α helix

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